title: Nucleostemin deletion reveals an essential mechanism that maintains the genomic stability of stem and progenitor cells.
abstract: Stem and progenitor cells maintain a robust DNA replication program during the tissue expansion phase of embryogenesis. The unique mechanism that protects them from the increased risk of replication-induced DNA damage, and hence permits self-renewal, remains unclear. To determine whether the genome integrity of stem/progenitor cells is safeguarded by mechanisms involving molecules beyond the core DNA repair machinery, we created a nucleostemin (a stem and cancer cell-enriched protein) conditional-null allele and showed that neural-specific knockout of nucleostemin predisposes embryos to spontaneous DNA damage that leads to severe brain defects in vivo. In cultured neural stem cells, depletion of nucleostemin triggers replication-dependent DNA damage and perturbs self-renewal, whereas overexpression of nucleostemin shows a protective effect against hydroxyurea-induced DNA damage. Mechanistic studies performed in mouse embryonic fibroblast cells showed that loss of nucleostemin triggers DNA damage and growth arrest independently of the p53 status or rRNA synthesis. Instead, nucleostemin is directly recruited to DNA damage sites and regulates the recruitment of the core repair protein, RAD51, to hydroxyurea-induced foci. This work establishes the primary function of nucleostemin in maintaining the genomic stability of actively dividing stem/progenitor cells by promoting the recruitment of RAD51 to stalled replication-induced DNA damage foci.
authors.affiliation: Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.
authors.forename: Lingjun
authors.initials: L
authors.lastname: Meng
authors.forename: Tao
authors.initials: T
authors.lastname: Lin
authors.forename: Guang
authors.initials: G
authors.lastname: Peng
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Hsu
authors.forename: Sun
authors.initials: S
authors.lastname: Lee
authors.forename: Shiaw-Yih
authors.initials: SY
authors.lastname: Lin
authors.forename: Robert Y L
authors.initials: RY
authors.lastname: Tsai
mesh_terms: D000483:Alleles; D000818:Animals; D004249:DNA Damage; D004261:DNA Replication; D005260:Female; D042822:Genomic Instability; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics*; D013234:Stem Cells / Q000166:cytology*
keywords: DNA damage repair; conditional knockout; homologous recombination; neural development; replication fork stalling